The proposed research is aimed at elucidating the mechanism of action of environmental neurotoxicants. Special emphasis will be placed on the action of heavy metals such as methylmercury on the excitability of nerve and muscle membranes with two specific goals: (1) In order to determine if the target site of methylmercury is at the nerve membrane ionic channels, the presynaptic transmitter release system, and/or the postsynaptic receptor/ionic channel complex, detailed electrophysiological experiments such as voltage clamp and noise analysis will be performed. Neuroblastoma cells will be used for the study of nerve membranes and postsynaptic membranes. Since these cells, originally derived from the mouse, possess well-defined ionic channels to produce action potentials and several types of receptors which can be analyzed by voltage clamp techniques, they serve as an excellent model with which the in-depth membrane mechanisms can be eluciated and whose data can be extrapolated to humans. Rat nerve-muscle preparations will also be used for the study of transmitter release and postsynaptic membranes as affected by methyl-mercury. Voltage clamp and noise analysis methods will be used for this purpose. (2) In order to determine what chemical groups in the membrane macromolecules are responsible for the methylmercury action, a variety of sulfhydryl and other protein specific reagents will be studied for their direct effects on neuroblastoma cells and rat neuromuscular preparations. The results of this study will have a gr@at impact not only on our overall view of mercury poisoning, but also on the ways to prevent and cure mercury poisoning. This will also set a solid prototype of the neurotoxicological study of evironmental toxicants at the cellular and membrane levels.